Mineralocorticoid receptor antagonists

ABSTRACT

The present invention is directed to compounds of the Formula (I) as well as pharmaceutically acceptable salts thereof that are possible useful for treating aldosterone-mediated diseases. The invention furthermore relates to processes for preparing compounds of the Formula (I), to their possible use for the treatment of the above mentioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical compositions which comprise compounds of the Formula (I).

RELATED APPLICATIONS

This application claims benefit to provisional application U.S. Ser. No.61/546,774, filed on 13 Oct. 2011, herein incorporated by reference.

BACKGROUND OF THE INVENTION

The Mineralocorticoid Receptor (MR) is a nuclear hormone receptor thatis activated by aldosterone and regulates the expression of many genesinvolved in electrolyte homeostasis and cardiovascular disease.Increased circulating aldosterone increases blood pressure through itseffects on natriuresis, with potentially additional effects on thebrain, heart and vasculature. In addition, hyperaldosteronism have beenlinked to many pathophysiological processes resulting in renal andcardiovascular disease. While hyperaldosteronism is commonly caused byaldosterone-producing adenomas, resistant hypertensive patientsfrequently suffer from increased aldosterone levels often termed as“Aldosterone Breakthrough” as a result of increases in serum potassiumor residual AT1R activity. Hyperaldosteronism and aldosteronebreakthrough typically results in increased MR activity and MRantagonists have been shown to be effective as anti-hypertensive agentsand also in the treatment of heart failure and primaryhyperaldosteronism.

In addition, in visceral tissues, such as the kidney and the gut, MRregulates sodium retention, potassium excretion and water balance inresponse to aldosterone. MR expression in the brain also appears to playa role in the control of neuronal excitability, in the negative feedbackregulation of the hypothalamic-pituitary-adrenal axis, and in thecognitive aspects of behavioral performance (Castren et al., J. ofNeuroendocrinology, 3, 461-66 (1993)).

Eplerenone and spironolactone are two MR antagonists that have beenshown to be efficacious in treating cardiovascular disease, particularlyhypertension and heart failure (RALES Investigators (1999) The Effect ofSpironolactone on Morbidity and Mortality in Patients with Severe HeartFailure, N. Engl. J. Med., 1999, 341(10):709-717; Pitt B, et al.,EPHESUS investigator (2003) Eplerenone, a Selective Aldosterone Blocker,in Patients with Left Ventricular Dysfunction After MyocardialInfarction, N. Engl. J. Med., 348(14):1309-1321; Funder J W., (2010)Eplerenone in Chronic Renal Disease: the EVALUATE trial, Hypertens.Res., 33(6):539-40.). Moreover, multiple studies have shown thattreatment with spironolactone or eplerenone significantly lower systolicblood pressure in mild-moderate, obese, systolic, PHA, and resistanthypertensive patients (Calhoun D A, et al., (2008) Effectiveness of theSelective Aldosterone Blocker, Eplerenone, in Patients with ResistantHypertension, J. Am. Soc. Hypertens., 2008 November-December;2(6):462-8; Huang B S, et al., (2010) Central Neuronal Activation andPressor Responses Induced by Circulating ANG II: role of the brainaldosterone-“ouabain” pathway, Am. J. Physiol. Heart. Circ. Physiol.,(2):H422-30; The RALES Investigators. (1996) Effectiveness ofSpironolactone added to an Angiotensin-converting enzyme Inhibitor and aLoop Diuretic for Severe Chronic Congestive Heart Failure, (TheRandomized Aldactone Evaluation Study [RALES]), Am. J. Cardiol., 1996;78:902-907; Pitt B, et al., EPHESUS Investigators, Serum potassium andclinical outcomes in the Eplerenone Post-Acute Myocardial InfarctionHeart Failure Efficacy and Survival Study (EPHESUS), Circulation, 2008Oct. 14; 118(16):1643-50; Bomback A S et al., (2009), Low-dosespironolactone, added to long-term ACE inhibitor therapy, reduces bloodpressure and urinary albumin excretion in obese patients withhypertensive target organ damage, Clin. Nephrol., 72(6):449-56; WilliamsJ S, Hypertension: spironolactone and resistant hypertension, Nat. Rev.Endocrinol., 2010 May; 6(5):248-50; Nishizaka M K, et al., The role ofaldosterone antagonists in the management of resistant hypertension.Curr Hypertens Rep. 2005 October; 7(5):343-7. Review; Gaddam K, et al.,(2010) Rapid reversal of left ventricular hypertrophy and intracardiacvolume overload in patients with resistant hypertension andhyperaldosteronism: a prospective clinical study, Hypertension,55(5):1137-42; Zannad F, et al., (2010) Rationale and design of theEplerenone in Mild Patients Hospitalization And Survival Study in HeartFailure (EMPHASIS-HF), Eur. J. Heart Fail., 12(6):617-22).

Evidence in preclinical models also suggests that MR antagonists wouldbe efficacious in treating the metabolic syndrome and atherosclerosis(Takai, S. et al, (2005) Eplerenone inhibits atherosclerosis in nonhumanprimates. Hypertension. 46(5):1135-9; Tirosh, A. et al., GK. (2010)Mineralocorticoid receptor antagonists and the metabolic syndrome. CurrHypertens Rep. 2010 August; 12(4):252-7).

Also, published PCT application WO 2002/17895 disclosed that aldosteroneantagonists are useful in the treatment of subjects suffering from oneor more cognitive dysfunctions including, but not limited to psychoses,cognitive disorders (such as memory disturbances), mood disorders (suchas depression and bipolar disorder), anxiety disorders and personalitydisorders.

Elevation in aldosterone levels, or excess stimulation ofmineralocorticoid receptors, is linked to several physiologicaldisorders or pathologic disease states, including Conn's Syndrome,primary and secondary hyperaldosteronism, increased sodium retention,increased magnesium and potassium excretion (diuresis), increased waterretention, hypertension (isolated systolic and combinedsystolic/diastolic), arrhythmias, myocardial fibrosis, myocardialinfarction, Bartter's Syndrome, and disorders associated with excesscatecholamine levels. (Hadley, M. E., ENDOCRINOLOGY, 2^(nd) Ed., pp.366-81, (1988); and Brilla et al., Journal of Molecular and CellularCardiology, 25 (5), pp. 563-75 (1993). Compounds and/or pharmaceuticalcompositions which act as MR antagonists might be expected to be ofvalue in the treatment of any of the above conditions. Despitesignificant therapeutic advances in the treatment of hypertension andheart failure, the current standard of care is suboptimal and there is aclear unmet medical need for additional therapeutic/pharmacologicalinterventions. This invention addresses those needs by providingcompounds and compositions, which antagonize the MR and potentially haveutility in the treatment or prevention of hypertension, heart failure,other cardiovascular disorders and other aldosterone disorders.

SUMMARY OF THE INVENTION

The present invention relates to compounds which have Mineralocorticoid

Receptor (MR) antagonist activity, which might be expected to bevaluable pharmaceutically active compounds for the possible treatment ofdiseases, for example for treating aldosterone-mediated disorders,including cardiovascular disease. The present invention is directed tocompounds of the Formula I:

or a pharmaceutically acceptable salt thereof. The invention furthermorerelates to possible methods of treating and preventing the abovementioned diseases and to processes for preparing compounds of theFormula I and for pharmaceutical preparations which comprise compoundsof Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The invention concerns compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

-   X is NH or O;-   Each R¹ is independently halo, CF₃, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,    or OR, wherein said alkyl and cycloalkyl are optionally substituted    with one to three groups selected from halo, OR, CF₃, or CN;-   Each R is independently H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or CF₃    wherein said alkyl and cycloalkyl are optionally substituted with    one to three groups selected from halo, OH, C₁-C₆ alkoxy, CF₃, or    CN;-   Each R^(a) is independently H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or    CF₃ wherein said alkyl, cycloalkyl and aryl are optionally    substituted with one to three groups selected from halo, OR, CF₃, or    CN;-   Each R^(b) is independently H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, CF₃,    or aryl, wherein said alkyl, cycloalkyl and aryl are optionally    substituted with one to three groups selected from halo, OR, CF₃, or    CN;-   R² is triazolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl,    isoxazolyl, thiadiazolyl or oxazolyl, where triazolyl, oxadiazolyl,    imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl or    oxazolyl is optionally substituted with one to two groups from R⁵;-   R⁴ is H, C₁-C₆ alkyl, aryl, or C₃-C₁₀ cycloalkyl, where said alkyl,    aryl, or cycloalkyl is optionally substituted with one to four    groups selected from halo or OR;-   Each R⁵ is independently OR, (CR^(c) ₂)₀₋₃—CF₃, C₁-C₆ alkyl, (CR^(c)    ₂)₀₋₃—C₃-C₁₀ cycloalkyl, (CR^(c) ₂)₀₋₃-aryl, (CR^(c)    ₂)₀₋₃-heteroaryl, or (CR^(c) ₂)₀₋₃-halo, where said alkyl,    cycloalkyl, aryl or heteroaryl is optionally substituted with one to    three groups selected from optionally substituted aryl, optionally    substituted heteroaryl, optionally substituted heterocyclyl, OR,    halo, CF₃ or NH₂; and wherein said optionally substituted aryl,    optionally substituted heteroaryl, or optionally substituted    heterocyclyl are optionally substituted one to four times by halo,    CF₃, NH₂ or OR.-   Each R^(c) is independently H, C₁-C₆ alkyl, or C₃-C₁₀ cycloalkyl,    wherein said alkyl and cycloalkyl are optionally substituted with    one to three groups selected from halo, OR, CF₃, or CN;-   m is 0, 1, 2 or 3; and-   p is 0, 1, 2 or 3.

In another embodiment of the compounds of Formula I or theirpharmaceutically acceptable salts,

-   X is NH or O;-   Each R¹ is independently halo, CF₃, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,    or OR, wherein said alkyl and cycloalkyl are optionally substituted    with one to three groups selected from halo, OR, CF₃, or CN;-   Each R is independently H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or CF₃    wherein said alkyl and cycloalkyl are optionally substituted with    one to three groups selected from halo, OR, CF₃, or CN;-   Each R^(a) is independently H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or    CF₃ wherein said alkyl, cycloalkyl and aryl are optionally    substituted with one to three groups selected from halo, OR, CF₃, or    CN;-   Each R^(b) is independently H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, CF₃,    or aryl, wherein said alkyl, cycloalkyl and aryl are optionally    substituted with one to three groups selected from halo, OR, CF₃, or    CN;-   R² is triazolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl,    isoxazolyl, thiadiazolyl or oxazolyl, where triazolyl, oxadiazolyl,    imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl or    oxazolyl is optionally substituted with one to two groups from R⁵;-   R⁴ is H, C₁-C₆ alkyl, aryl, or C₃-C₁₀ cycloalkyl, where said alkyl,    aryl, or cycloalkyl is optionally substituted with one to four    groups selected from halo or OR;-   Each R⁵ is independently OR, (CR^(c) ₂)₀₋₃—CF₃, C₁-C₆ alkyl, (CR^(c)    ₂)₀₋₃—C₃-C₁₀ cycloalkyl, (CR^(c) ₂)₀₋₃-aryl, (CR^(c)    ₂)₀₋₃-heteroaryl, or (CR^(c) ₂)₀₋₃-halo, where said alkyl,    cycloalkyl, aryl or heteroaryl is optionally substituted with one to    three groups selected from aryl, heteroaryl, heterocyclyl, OR, halo,    CF₃ or NH₂;-   Each R^(c) is independently H, C₁-C₆ alkyl, or C₃-C₁₀ cycloalkyl,    wherein said alkyl and cycloalkyl are optionally substituted with    one to three groups selected from halo, OR, CF₃, or CN;-   m is 0, 1, 2 or 3; and-   p is 0, 1, 2 or 3.

In another embodiment of the compounds of Formula I,

-   Each R^(a) is independently H or C₁-C₆ alkyl wherein said alkyl is    optionally substituted with one to three groups selected from halo,    OR, CF₃, or CN;-   R² is triazolyl, oxadiazolyl, imidazolyl or oxazolyl, where    triazolyl, oxadiazolyl, imidazolyl or oxazolyl is optionally    substituted with one to two groups from R⁵;-   R⁴ is aryl or C₃-C₁₀ cycloalkyl, where said aryl or cycloalkyl is    optionally substituted with one to four groups selected from halo or    OR;-   Each R⁵ is independently OR, C₁-C₆ alkyl, (CR₂)₀₋₃—C₃-C₁₀    cycloalkyl, (CR₂)₀₋₃-aryl, (CR₂)₀₋₃-heteroaryl, or (CR₂)₀₋₃-halo,    where said alkyl, cycloalkyl, aryl or heteroaryl is optionally    substituted with one to three groups selected from aryl, heteroaryl,    or heterocyclyl;-   m is 0 or 1;-   p is 0, 1 or 2;-   and all other variables are as previously defined in Formula I.

In a further embodiment, the invention is directed to compounds ofFormula I having structural Formula II:

or a pharmaceutically acceptable salt thereof, wherein

-   Each R¹ is independently halo, CF₃, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,    or OR, wherein said alkyl and cycloalkyl are optionally substituted    with one to three groups selected from halo, OR, CF₃, or CN;-   Each R is independently H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or CF₃    wherein said alkyl and cycloalkyl are optionally substituted with    one to three groups selected from halo, OH, C₁-C₆ alkoxy, CF₃, or    CN;-   Each R^(b) is independently H or C₁-C₆ alkyl, wherein said alkyl is    optionally substituted with one to three groups selected from halo,    OR, CF₃, or CN;-   Each R^(c) is independently H, C₁-C₆ alkyl, or C₃-C₁₀ cycloalkyl,    wherein said alkyl and cycloalkyl are optionally substituted with    one to three groups selected from halo, OR, CF₃, or CN;-   R² is triazolyl, oxadiazolyl, imidazolyl or oxazolyl, where    triazolyl, oxadiazolyl, imidazolyl or oxazolyl is optionally    substituted with one to two groups from R⁵;-   R⁴ is C₁-C₆ alkyl, aryl, or C₃-C₁₀ cycloalkyl, where said alkyl,    aryl, or cycloalkyl is optionally substituted with one to four    groups selected from halo or OR;-   Each R⁵ is independently (CR^(c) ₂)₀₋₃—CF₃, C₁-C₆ alkyl, (CR^(c)    ₂)₀₋₃—C₃-C₁₀ cycloalkyl, (CR^(c) ₂)₀₋₃-aryl, (CR^(c)    ₂)₀₋₃-heteroaryl, or (CR^(c) ₂)₀₋₃-halo, where said alkyl,    cycloalkyl, aryl or heteroaryl is optionally substituted with one to    three groups selected from aryl, heteroaryl, heterocyclyl, OR, halo,    CF₃ or NH₂;-   m is 0 or 1; and-   p is 1 or 2.

In another embodiment of Formula II,

-   Each R^(b) is independently H or C₁-C₆ alkyl;-   R⁴ is aryl, or C₃-C₁₀ cycloalkyl, where said aryl, or cycloalkyl is    optionally substituted with one to four groups selected from halo or    OR;-   Each R⁵ is independently (CR^(c) ₂)₀₋₃—C₃-C₁₀ cycloalkyl, (CR^(c)    ₂)₀₋₃-aryl, or (CR^(c) ₂)₀₋₃-heteroaryl, where said alkyl,    cycloalkyl, aryl or heteroaryl is optionally substituted with one to    three groups selected from aryl, heteroaryl, heterocyclyl, OR, halo,    CF₃ or NH₂;-   p is 1;-   and all other variables are as previously defined in Formula II.

In an embodiment, a compound which is

Compound Number IUPAC Name 15-Benzyl-5-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione 2(5R)-5-Benzyl-5-[5-(3,5-dimethoxybenzyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 3(5R)-5-Benzyl-5-(5-benzyl-1,3,4-oxadiazol-2-yl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 4(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 5(5R)-5-Benzyl-5-[5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 6(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,3-oxazolidine-2,4-dione 7(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-pyridin-4-yl-1,3,4-oxadiazol-2-yl)-1,3-oxazolidine-2,4-dione 8(5R)-5-Benzyl-5-[5-(4,6-dimethoxypyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 9(5R)-5-Benzyl-5-{5-[1-(3,5-difluorophenyl)cyclopropyl]-1,3,4-oxadiazol-2-yl}-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 10(5R)-5-[5-(3-Amino-5-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-5-benzyl-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 11(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]-1,3-oxazolidine-2,4-dione 12(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-{5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl}-1,3-oxazolidine-2,4-dione13 (5R)-5-Benzyl-5-[5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 14(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-[5-(1-pyridin-4-ylcyclopropyl)-1,3,4-oxadiazol-2-yl]-1,3-oxazolidine-2,4-dione 15(5R)-5-Benzyl-5-[4-(3,5-dimethoxyphenyl)-1H-imidazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 16(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-1H-imidazol-2-yl)-1,3-oxazolidine-2,4-dione 17(5R)-5-Benzyl-5-(5-benzyl-1H-imidazol-2-yl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 18(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(4-phenyl-1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione 19(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione 20(5R)-5-Benzyl-5-(5-benzyl-1,3-oxazol-2-yl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 21(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(3-phenyl-1H-1,2,4-triazol-5-yl)-1,3-oxazolidine-2,4-dione 22(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dioneor a pharmaceutically acceptable salt thereof.

In a further embodiment, a compound which is

Compound Number IUPAC Name 15-Benzyl-5-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione 2(5R)-5-Benzyl-5-[5-(3,5-dimethoxybenzyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 3(5R)-5-Benzyl-5-(5-benzyl-1,3,4-oxadiazol-2-yl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 4(5R)-5-Benzyl-5-[5-(3,5-dimethoxypheny)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 5(5R)-5-Benzyl-5-[5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 8(5R)-5-Benzyl-5-[5-(4,6-dimethoxypyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 13(5R)-5-Benzyl-5-[5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 15(5R)-5-Benzyl-5-[4-(3,5-dimethoxyphenyl)-1H-imidazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 22(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dioneor a pharmaceutically acceptable salt thereof.

As used herein except where noted, “alkyl” is intended to include bothbranched- and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. The term “cycloalkyl” meanscarbocycles containing no heteroatoms. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,decahydronaphthyl and the like. Commonly used abbreviations for alkylgroups are used throughout the specification, e.g. methyl may berepresented by conventional abbreviations including “Me” or CH₃ or asymbol that is an extended bond without defined terminal group, e.g.

ethyl may be represented by “Et” or CH₂CH₃, propyl may be represented by“Pr” or CH₂CH₂CH₃, butyl may be represented by “Bu” or CH₂CH₂CH₂CH₃,etc. “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) for example, means linear orbranched chain alkyl groups, including all isomers, having the specifiednumber of carbon atoms. C₁₋₆ alkyl includes all of the hexyl alkyl andpentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- andisopropyl, ethyl and methyl. “C₁₋₄ alkyl” means n-, iso-, sec- andt-butyl, n- and isopropyl, ethyl and methyl. If no number is specified,1-10 carbon atoms are intended for linear or branched alkyl groups. Thephrase “C₁₋₆ alkyl, wherein the alkyl group may be unsubstituted orsubstituted with 1-3 fluorine atoms” refers to alkyl groups having 0, 1,2 or 3 fluorine atoms attached to one or more carbon atoms. The group“CF₃”, for example, is a methyl group having three fluorine atomsattached the same carbon atom.

As used herein, “C₁₋₆ alkoxy” refers to an alkyl group bonded to anoxygen. For example, C₁ alkoxy is methoxy group (—OCH₃), C₂ alkoxy is anethoxy group (—OCH₂CH₃) and the like.

“Aryl” unless otherwise indicated, means mono- and bicyclic aromaticrings containing 6-12 carbon atoms. Examples of aryl include, but arenot limited to, phenyl, naphthyl, indenyl and the like. “Aryl” alsoincludes monocyclic rings fused to an aryl group. Examples includedihydroindenyl, tetrahydronaphthalenyl, indanyl and the like. In anembodiment, the preferred aryl is phenyl.

“Heteroaryl” unless otherwise indicated, means a mono- or bicyclicaromatic ring or ring system having 5 to 10 atoms and containing atleast one heteroatom selected from O, S and N. Examples include, but arenot limited to, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl,pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl,pyrimidinyl, pyridazinyl, pyrazinyl, and the like. Heteroaryl alsoincludes aromatic heterocyclic groups fused to heterocycles that arenon-aromatic or partially aromatic, and aromatic heterocyclic groupsfused to cycloalkyl rings. Additional examples of heteroaryls include,but are not limited to, indazolyl, thienopyrazolyl, imidazopyridazinyl,pyrazolopyrazolyl, pyrazolopyridinyl, imidazopyridinyl andimidazothiazolyl. Heteroaryl also includes such groups in charged form,e.g., pyridinium. In an embodiment, heteroaryl is oxadiazolyl,pyrazolyl, oxazolyl, pyridinyl and imidazolyl

“Heterocyclyl”, unless otherwise indicated, means a 4-, 5- or 6-memberedmonocyclic saturated ring containing at least one heteroatom selectedfrom N, S and O, in which the point of attachment may be carbon ornitrogen. Examples of “heterocyclyl” include, but are not limited to,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,oxazolidinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl,benzoxazinyl, and the like. The term also includes partially unsaturatedmonocyclic rings that are not aromatic, such as 2- or 4-pyridonesattached through the nitrogen orN-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils).Heterocyclyl moreover includes such moieties in charged form, e.g.,piperidinium. In an embodiment, heterocyclyl is pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and oxazolidinyl.

“Halogen (or halo)” unless otherwise indicated, includes fluorine(fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In oneembodiment, halo is fluorine or chlorine.

By “oxo” is meant the functional group “═O” which is an oxygen atomconnected to the molecule via a double bond, such as, for example, (1)“C═(O)”, that is a carbonyl group; (2) “S═(O)”, that is, a sulfoxidegroup; and (3) “N═(O)”, that is, an N-oxide group, such aspyridyl-N-oxide.

Unless expressly stated to the contrary, substitution by a namedsubstituent is permitted on any atom in a ring (e.g., aryl, a heteroarylring, or a saturated heterocyclic ring) provided such ring substitutionis chemically allowed and results in a stable compound. A “stable”compound is a compound which can be prepared and isolated and whosestructure and properties remain or can be caused to remain essentiallyunchanged for a period of time sufficient to allow use of the compoundfor the purposes described herein (e.g., therapeutic or prophylacticadministration to a subject).

Reference to the compounds of structural Formula I includes thecompounds of other generic structural Formulae that fall within thescope of Formula I, including but not limited to Formula II.

When any variable (e.g., R, R^(a), R¹, etc.) occurs more than one timein any constituent or in Formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R^(a), R^(b),R¹, R², etc., are to be chosen in conformity with well-known principlesof chemical structure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substituent. Where multiple substituent moietiesare disclosed or claimed, the substituted compound can be independentlysubstituted by one or more of the disclosed or claimed substituentmoieties, singly or plurally. By independently substituted, it is meantthat the (two or more) substituents can be the same or different.

Where a substituent or variable has multiple definitions, it isunderstood that the substituent or variable is defined as being selectedfrom the group consisting of the indicated definitions.

Optical Isomers—Diastereoisomers—GeometricIsomers—Tautomers—Atropisomers:

Compounds of structural Formula I may contain one or more asymmetriccenters and can thus occur as racemates and racemic mixtures, singleenantiomers, diastereoisomeric mixtures and individual diastereoisomers.The present invention is meant to comprehend all such isomeric forms ofthe compounds of structural Formula I.

Compounds of structural Formula I may be separated into their individualdiastereoisomers by, for example, fractional crystallization from asuitable solvent, for example methanol or ethyl acetate or a mixturethereof, or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration.

Alternatively, any stereoisomer or isomers of a compound of the generalstructural Formula I may be obtained by stereospecific synthesis usingoptically pure starting materials or reagents of known absoluteconfiguration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

For compounds described herein which contain olefinic double bonds,unless specified otherwise, they are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers which havedifferent points of attachment of hydrogen accompanied by one or moredouble bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention.

In the compounds of structural Formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofstructural Formula I. For example, different isotopic forms of hydrogen(H) include protium (¹H) and deuterium (²H, also denoted as D). Protiumis the predominant hydrogen isotope found in nature. Enriching fordeuterium may afford certain therapeutic advantages, such as increasingin vivo half-life or reducing dosage requirements, or may provide acompound useful as a standard for characterization of biologicalsamples. Isotopically-enriched compounds within structural Formula I,can be prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates. Thus, the presentinvention covers isotopically-enriched compounds, including deuteratedcompounds.

The present invention includes all stereoisomeric forms of the compoundsof the Formula I. Centers of asymmetry that are present in the compoundsof Formula I can all independently of one another have S configurationor R configuration. The invention includes all possible enantiomers anddiastereomers and mixtures of two or more stereoisomers, for examplemixtures of enantiomers and/or diastereomers, in all ratios. Thus,enantiomers are a subject of the invention in enantiomerically pureform, both as levorotatory and as dextrorotatory antipodes, in the formof racemates and in the form of mixtures of the two enantiomers in allratios. In the case of a cis/trans isomerism, the invention includesboth the cis form and the trans form as well as mixtures of these formsin all ratios. The preparation of individual stereoisomers can becarried out, if desired, by separation of a mixture by customarymethods, for example by chromatography or crystallization, by the use ofstereochemically uniform starting materials for the synthesis or bystereoselective synthesis. Optionally a derivatization can be carriedout before a separation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at the stage of the compounds of theFormula I or at the stage of an intermediate during the synthesis. Thepresent invention also includes all tautomeric forms of the compounds ofFormula I.

The present invention includes all atropisomer forms of the compounds ofFormula I. Atropisomers are stereoisomers resulting from hinderedrotation about single bonds where the steric strain barrier to rotationis high enough to allow for the isolation of the conformers.Atropisomers display axial chirality. Separation of atropisomers ispossibly by chiral resolution methods such as selective crystallization.

Salts:

It will be understood that, as used herein, references to the compoundsof structural Formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate, ascorbate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, propionate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, thiocyanate,tosylate, triethiodide, valerate and the like. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof include, but are not limitedto, salts derived from inorganic bases including aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,mangamous, potassium, sodium, zinc, and the like. Particularly preferredare the ammonium, calcium, magnesium, potassium, and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, cyclic amines,dicyclohexyl amines and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and β-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

Solvates and the hydrates of the compounds of structural Formula I areincluded in the present invention as well.

If the compounds of Formula I simultaneously contain acidic and basicgroups in the molecule the invention also includes, in addition to thesalt forms mentioned, inner salts or betaines (zwitterions). Salts canbe obtained from the compounds of Formula I by customary methods whichare known to the person skilled in the art, for example by combinationwith an organic or inorganic acid or base in a solvent or dispersant, orby anion exchange or cation exchange from other salts. The presentinvention also includes all salts of the compounds of Formula I which,owing to low physiological compatibility, are not directly suitable foruse in pharmaceuticals but which can be used, for example, asintermediates for chemical reactions or for the preparation ofpharmaceutically acceptable salts.

As appropriate, the following embodiments may apply to structuralFormulae I and/or II.

In an embodiment, R¹ is independently halo, C₁-C₆ alkyl, or OR, whereinsaid alkyl is optionally substituted with one to three groups selectedfrom halo, OR, CF₃, or CN. In a further embodiment, R¹ is independentlyhalo or C₁-C₆ alkyl. In another embodiment, R¹ is independently halo.

In an embodiment, each R^(a) is independently H or C₁-C₆ alkyl, whereinsaid alkyl is optionally substituted with one to three groups selectedfrom C₁-C₆ alkyl, halo, OR, CF₃, or CN. In another embodiment, eachR^(a) is H.

In an embodiment, each R^(b) is independently H, C₁-C₆ alkyl, or C₃-C₁₀cycloalkyl, wherein said alkyl and cycloalkyl are optionally substitutedwith one to three groups selected from halo, OR, CF₃, or CN. In anotherembodiment, each R^(b) is independently H or C₁-C₆ alkyl, wherein saidalkyl is optionally substituted with one to three groups selected fromhalo, OR, CF₃, or CN. In a further embodiment, each R^(b) isindependently H or C₁-C₆ alkyl.

In an embodiment, R² is triazolyl, oxadiazolyl, imidazolyl or oxazolyl,where triazolyl, oxadiazolyl, imidazolyl or oxazolyl is optionallysubstituted with one to two groups from R⁵.

In an embodiment, R⁴ is C₁-C₆ alkyl, aryl, or C₃-C₁₀ cycloalkyl, wheresaid alkyl, aryl, or cycloalkyl is optionally substituted with one tofour groups selected from halo or OR. In another embodiment, R⁴ is arylor C₃-C₁₀ cycloalkyl, where said aryl, or cycloalkyl is optionallysubstituted with one to four groups selected from halo or OR. In furtherembodiment, R⁴ is aryl, where said aryl is optionally substituted withone to four groups selected from halo or OR. In further embodiment, R⁴is phenyl, where said aryl is optionally substituted with one to twogroups selected from halo or OR.

In an embodiment, R⁵ is independently C₁-C₆ alkyl, (CR^(c) ₂)₀₋₃—C₃-C₀cycloalkyl, (CR^(c) ₂)₀₋₃-aryl, or (CR^(c) ₂)₀₋₃-heteroaryl, where saidalkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted withone to three aryl, heteroaryl, heterocyclyl, OR, halo, CF₃ or NH₂groups. In another embodiment, R⁵ is independently (CR^(c) ₂)₀₋₃—C₃-C₁₀cycloalkyl, (CR^(c) ₂)₀₋₃-aryl, or (CR^(c) ₂)₀₋₃-heteroaryl, where saidcycloalkyl, aryl or heteroaryl is optionally substituted with one tothree aryl, heteroaryl, heterocyclyl, OR, halo, CF₃ or NH₂ groups. Infurther embodiment, R⁵ is independently (CR^(c) ₂)₀₋₃—C₃-C₀ cycloalkyl,(CR^(c) ₂)₀₋₃-aryl, or (CR^(c) ₂)₀₋₃-heteroaryl, where said cycloalkyl,aryl or heteroaryl is optionally substituted with one to three OR, aryl,heteroaryl, heterocyclyl, or halo groups.

In an embodiment, m is 0, 1 or 2. In a further embodiment, m is 0 or 1.

In an embodiment, p is 1, 2 or 3. In a further embodiment, p is 1.

The present invention also relates to processes for the preparation ofthe compounds of Formula I which are described in the following and bywhich the compounds of the invention are obtainable.

The compounds of the Formula I according to the invention competitivelyantagonize the aldosterone receptor (MR) and they therefore might beuseful agents for the therapy of disorders related to increasedaldosterone levels. The ability for the compounds of Formula I toantagonize MR can be examined, for example, in the activity assaydescribed below.

One aspect of the invention that is of interest relates to a compound inaccordance with Formula I or a pharmaceutically acceptable salt thereofwhich might be useful in a method of treatment of the human or animalbody by therapy.

Another aspect of the invention that is of interest relates to acompound in accordance with Formula I or a pharmaceutically acceptablesalt thereof which might be useful as an anti-hypertensive agent in ahuman or animal.

Another aspect of the invention that is of interest is a possible methodof treating cardiovascular disease, heart failure, hypertension,atherosclerosis, primary hyperaldosternoism or a related condition in ahuman patient in need of such treatment comprising administering atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof.

Another aspect of the invention that is of interest relates to apossible method of treating metabolic syndrome in a mammal in need ofsuch treatment, comprising administering a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof.

Another aspect of the invention that is of interest relates to apossible method of treating a physiological or pathologic disease,selected from including Conn's Syndrome, primary and secondaryhyperaldosteronism, increased sodium retention, increased magnesium andpotassium excretion (diuresis), increased water retention, hypertension(isolated systolic and combined systolic/diastolic), arrhythmias,myocardial fibrosis, myocardial infarction, Bartter's Syndrome, anddisorders associated with excess catecholamine levels in a human patientin need of such treatment comprising administering to the patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof.

Another aspect of the invention that is of interest is a possible methodof treating renal failure in a human patient in need of such treatmentcomprising administering a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the invention that is of interest is a possible methodof treating hypertension, including, but not limited to, essentialhypertension, resistant hypertension, systolic hypertension, pulmonaryarterial hypertension, and the like.

Additionally, another aspect of the invention is a possible method oftreating hypertension in an obese animal or human.

Additionally, another aspect of the invention is a possible method oftreating hypertension in a diabetic animal or human.

Another aspect of the present invention is the possible use of thecompounds of Formula I and their pharmaceutically acceptable salts inthe prevention or prophylaxis of one or more disease states associatedwith inhibiting the MR in a mammal by administering an effective amountof a compound of Formula I or a pharmaceutically acceptable salt to amammal in need thereof.

The compounds of the Formula I and their pharmaceutically acceptablesalts can be administered to animals, preferably to mammals, and inparticular to humans, as pharmaceuticals by themselves, in mixtures withone another or in the form of pharmaceutical preparations. The term“patient” includes animals, preferably mammals and especially humans,who use the instant active agents for the prevention or treatment of amedical condition. Administering of the drug to the patient includesboth self-administration and administration to the patient by anotherperson. The patient may be in need of treatment for an existing diseaseor medical condition, or may desire prophylactic treatment (prevention)to prevent or reduce the risk of said disease or medical condition.

A subject of the present invention therefore also are the compounds ofthe Formula I and their pharmaceutically acceptable salts for use aspharmaceuticals, their use for antagonizing mineralocorticoid receptorsand in particular their use in the therapy and prophylaxis of theabovementioned syndromes as well as their potential use for preparingmedicaments for these purposes.

The terms “therapeutically effective (or efficacious) amount” andsimilar descriptions such as “an amount efficacious for treatment” areintended to mean that amount of a pharmaceutical drug that will elicitthe biological or medical response of a tissue, a system, animal orhuman that is being sought by a researcher, veterinarian, medical doctoror other clinician. The terms “prophylactically effective (orefficacious) amount” and similar descriptions such as “an amountefficacious for prevention” are intended to mean that amount of apharmaceutical drug that will prevent or reduce the risk of occurrenceof the biological or medical event that is sought to be prevented in atissue, a system, animal or human by a researcher, veterinarian, medicaldoctor or other clinician. The terms “preventing” or “prevention” asused herein refer to administering a compound of Formula I or itspharmaceutically acceptable salt before the onset of clinical symptoms.As an example, the dosage a patient receives can be selected so as toachieve the desired reduction in blood pressure; the dosage a patientreceives may also be titrated over time in order to reach a target bloodpressure. The dosage regimen utilizing a compound of the instantinvention is selected in accordance with a variety of factors includingtype, species, age, weight, sex and medical condition of the patient;the severity of the condition to be treated; the potency of the compoundchosen to be administered; the route of administration; and the renaland hepatic function of the patient. A consideration of these factors iswell within the purview of the ordinarily skilled clinician for thepurpose of determining the therapeutically effective or prophylacticallyeffective dosage amount needed to prevent, counter, or arrest theprogress of the condition. It is understood that a specific daily dosageamount can simultaneously be both a therapeutically effective amount,e.g., for treatment of hypertension, and a prophylactically effectiveamount, e.g., for prevention of myocardial infarction.

Furthermore, a subject of the present invention are pharmaceuticalpreparations (or pharmaceutical compositions) which comprise as activecomponent an effective dose of at least one compound of the Formula Iand/or a pharmaceutically acceptable salt thereof and a customarypharmaceutically acceptable carrier, i.e., one or more pharmaceuticallyacceptable carrier substances and/or additives.

Thus, subjects of the invention are, for example, said compound and itspharmaceutically acceptable salts for use as a pharmaceutical,pharmaceutical preparations which comprise as an active component atherapeutically effective dose of said compound and/or apharmaceutically acceptable salt thereof and a customarypharmaceutically acceptable carrier, and the uses of said compoundand/or a pharmaceutically acceptable salt thereof in the therapy orprophylaxis of the abovementioned syndromes as well as their use forpreparing medicaments for these purposes.

The pharmaceutical compositions according to the invention can beadministered orally, for example in the form of pills, tablets,lacquered tablets, sugar-coated tablets, granules, hard and soft gelatincapsules, aqueous, alcoholic or oily solutions, syrups, emulsions orsuspensions, or rectally, for example in the form of suppositories.Administration can also be carried out parenterally, for examplesubcutaneously, intramuscularly or intravenously in the form ofsolutions for injection or infusion. Other suitable administration formsare, for example, percutaneous or topical administration, for example inthe form of ointments, tinctures, sprays or transdermal therapeuticsystems, or the inhalative administration in the form of nasal sprays oraerosol mixtures, or, for example, microcapsules, implants or rods. Thepreferred administration form depends, for example, on the disease to betreated and on its severity.

The amount of active compound of the Formula I and/or itspharmaceutically acceptable salts in the pharmaceutical preparationsnormally is from 0.2 to 700 mg, preferably from 1 to 500 mg, per dose,but depending on the type of the pharmaceutical preparation it can alsobe higher. The pharmaceutical preparations usually comprise 0.5 to 90percent by weight of the compounds of the Formula I and/or theirpharmaceutically acceptable salts. The preparation of the pharmaceuticalpreparations can be carried out in a manner known per se. For thispurpose, one or more compounds of the Formula I and/or theirpharmaceutically acceptable salts, together with one or more solid orliquid pharmaceutical carrier substances and/or additives (or auxiliarysubstances) and, if desired, in combination with other pharmaceuticallyactive compounds having therapeutic or prophylactic action, are broughtinto a suitable administration form or dosage form which can then beused as a pharmaceutical in human or veterinary medicine.

For the production of pills, tablets, sugar-coated tablets and hardgelatin capsules it is possible to use, for example, lactose, starch,for example maize starch, or starch derivatives, talc, stearic acid orits salts, etc. Carriers for soft gelatin capsules and suppositoriesare, for example, fats, waxes, semisolid and liquid polyols, natural orhardened oils, etc. Suitable carriers for the preparation of solutions,for example of solutions for injection, or of emulsions or syrups are,for example, water, physiologically sodium chloride solution, alcoholssuch as ethanol, glycerol, polyols, sucrose, invert sugar, glucose,mannitol, vegetable oils, etc. It is also possible to lyophilize thecompounds of the Formula I and their pharmaceutically acceptable saltsand to use the resulting lyophilisates, for example, for preparingpreparations for injection or infusion. Suitable carriers formicrocapsules, implants or rods are, for example, copolymers of glycolicacid and lactic acid.

Besides the active compounds and carriers, the pharmaceuticalpreparations can also contain customary additives, for example fillers,disintegrants, binders, lubricants, wetting agents, stabilizers,emulsifiers, dispersants, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants.

The dosage of the active compound of the Formula I to be administeredand/or of a pharmaceutically acceptable salt thereof depends on theindividual case and is, as is customary, to be adapted to the individualcircumstances to achieve an optimum effect. Thus, it depends on thenature and the severity of the disorder to be treated, and also on thesex, age, weight and individual responsiveness of the human or animal tobe treated, on the efficacy and duration of action of the compoundsused, on whether the therapy is acute or chronic or prophylactic, or onwhether other active compounds are administered in addition to compoundsof the Formula I. In general, a daily dose of approximately 0.01 to 100mg/kg, preferably 0.01 to 10 mg/kg, in particular 0.3 to 5 mg/kg (ineach case mg per kg of bodyweight) is appropriate for administration toan adult weighing approximately 75 kg in order to obtain the desiredresults. The daily dose can be administered in a single dose or, inparticular when larger amounts are administered, be divided intoseveral, for example two, three or four individual doses. In some cases,depending on the individual response, it may be necessary to deviateupwards or downwards from the given daily dose.

The compounds of the Formula I bind to the mineralocorticoid receptorand antagonize the biological effects of aldosterone and cortisol. Onaccount of this property, apart from use as pharmaceutically activecompounds in human medicine and veterinary medicine, they can also beemployed as a scientific tool or as aid for biochemical investigationsin which such an effect on the mineralocorticoid receptor is intended,and also for diagnostic purposes, for example in the in vitro diagnosisof cell samples or tissue samples. The compounds of the Formula I andsalts thereof can furthermore be employed, as already mentioned above,as intermediates for the preparation of other pharmaceutically activecompounds.

The above-mentioned compounds are also of use in combination with otherpharmacologically active compounds. Additional active compounds that maybe used in combination with the compounds of the instant invention,either co-administered or in a fixed combination, include, but are notlimited to the following pharmaceutically acceptable salts, metabolites,solvates, prodrugs or polymorphs thereof: angiotensin converting enzymeinhibitors (e.g, alacepril, benazepril, captopril, ceronapril,cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril,lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril,temocapril, or trandolapril), angiotensin II receptor antagonists (e.g.,losartan, valsartan, candesartan, olmesartan, telmesartan), neutralendopeptidase inhibitors (e.g., enalkrein, RO 42-5892, A 65317, CP80794, ES 1005, ES 8891, SQ 34017, aliskiren(2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635), endothelin receptorantagonists, vasodilators, calcium channel blockers (e.g., amlodipine,nifedipine, veraparmil, diltiazem, gallopamil, niludipine, nimodipins,nicardipine), potassium channel activators (e.g., nicorandil, pinacidil,cromakalim, minoxidil, aprilkalim, loprazolam), diuretics (e.g.,hydrochlorothiazide, chlorthalidone, furosemide), sympatholitics,beta-adrenergic blocking drugs (e.g., propranolol, atenolol, bisoprolol,carvedilol, metoprolol, or metoprolol tartate), alpha adrenergicblocking drugs (e.g., doxazocin, prazocin or alpha methyldopa) centralalpha adrenergic agonists, peripheral vasodilators (e.g. hydralazine),lipid lowering agents (e.g., niacin, HMG Co-A reductase inhibitors),metabolic altering agents including insulin sensitizing agents andrelated compounds (e.g., muraglitazar, glipizide, metformin,rosiglitazone) or with other drugs beneficial for the prevention or thetreatment of the above-mentioned diseases including nitroprusside anddiazoxide.

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) PPAR gamma agonists and partial agonists, including both glitazonesand non-glitazones (e.g. troglitazone, pioglitazone, englitazone,MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512,LY-818, and compounds disclosed in WO02/08188, WO2004/020408, andWO2004/020409.

(b) biguanides, such as metformin and phenformin;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(d) dipeptidyl peptidase-IV (DPP-4) inhibitors, such as sitagliptin,saxagliptin, vildagliptin, and alogliptin;

(e) insulin or insulin mimetics;

(f) sulfonylureas such as tolbutamide, glimepiride, glipizide, andrelated materials;

(g) α-glucosidase inhibitors (such as acarbose);

(h) agents which improve a patient's lipid profile, such as (i) HMG-CoAreductase inhibitors (lovastatin, simvastatin, rosuvastatin,pravastatin, fluvastatin, atorvastatin, rivastatin, pitavastatin,ZD-4522 and other statins), (ii) bile acid sequestrants (cholestyramine,colestipol, and dialkylaminoalkyl derivatives of a cross-linkeddextran), (iii) niacin receptor agonists, nicotinyl alcohol, nicotinicacid, or a salt thereof, (iv) PPARα agonists, such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v)cholesterol absorption inhibitors, such as ezetimibe, (vi) acylCoA:cholesterol acyltransferase (ACAT) inhibitors, such as avasimibe,(vii) CETP inhibitors, such as torcetrapib, anacetrapib, anddalcetrapib, and (viii) phenolic antioxidants, such as probucol;

(i) PPARα/γ dual agonists, such as muraglitazar, tesaglitazar,farglitazar, and JT-501;

(j) PPARδ agonists, such as those disclosed in WO97/28149;

(k) anti-obesity compounds, such as fenfluramine, dexfenfluramine,phentiramine, subitramine, orlistat, neuropeptide Y Y5 inhibitors, MC4Ragonists, cannabinoid receptor 1 (CB-1) antagonists/inverse agonists(e.g., rimonabant and taranabant), and β₃ adrenergic receptor agonists;

(l) ileal bile acid transporter inhibitors;

(m) agents intended for use in inflammatory conditions, such as aspirin,non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, andcyclooxygenase-2 (Cox-2) selective inhibitors;

(n) glucagon receptor antagonists;

(o) GLP-1;

(p) GIP-1;

(q) GLP-1 analogs and derivatives, such as exendins, (e.g., exenatideand liruglatide), and

(r) 11β-hydroxysteroid dehydrogenase-1 (HSD-1) inhibitors.

One or more additional active agents may be administered with thecompounds described herein. The additional active agent or agents can belipid modifying compounds or agents having other pharmaceuticalactivities, or agents that have both lipid-modifying effects and otherpharmaceutical activities. Examples of additional active agents whichmay be employed include but are not limited to HMG-CoA reductaseinhibitors, which include statins in their lactonized or dihydroxy openacid forms and pharmaceutically acceptable salts and esters thereof,including but not limited to lovastatin (see U.S. Pat. No. 4,342,767),simvastatin (see U.S. Pat. No. 4,444,784), dihydroxy open-acidsimvastatin, particularly the ammonium or calcium salts thereof,pravastatin, particularly the sodium salt thereof (see U.S. Pat. No.4,346,227), fluvastatin particularly the sodium salt thereof (see U.S.Pat. No. 5,354,772), atorvastatin, particularly the calcium salt thereof(see U.S. Pat. No. 5,273,995), pitavastatin also referred to as NK-104(see PCT international publication number WO 97/23200) and rosuvastatin,also known as CRESTOR®; see U.S. Pat. No. 5,260,440); HMG-CoA synthaseinhibitors; squalene epoxidase inhibitors; squalene synthetaseinhibitors (also known as squalene synthase inhibitors), acyl-coenzymeA: cholesterol acyltransferase (ACAT) inhibitors including selectiveinhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors of ACAT-1 and-2; microsomal triglyceride transfer protein (MTP) inhibitors;endothelial lipase inhibitors; bile acid sequestrants; LDL receptorinducers; platelet aggregation inhibitors, for example glycoproteinIIb/IIIa fibrinogen receptor antagonists and aspirin; human peroxisomeproliferator activated receptor gamma (PPAR-gamma) agonists includingthe compounds commonly referred to as glitazones for examplepioglitazone and rosiglitazone and, including those compounds includedwithin the structural class known as thiazolidine diones as well asthose PPAR-gamma agonists outside the thiazolidine dione structuralclass; PPAR-alpha agonists such as clofibrate, fenofibrate includingmicronized fenofibrate, and gemfibrozil; vitamin B₆ (also known aspyridoxine) and the pharmaceutically acceptable salts thereof such asthe HCl salt; vitamin B₁₂ (also known as cyanocobalamin); folic acid ora pharmaceutically acceptable salt or ester thereof such as the sodiumsalt and the methylglucamine salt; anti-oxidant vitamins such as vitaminC and E and beta carotene; beta-blockers; diuretics (e.g.,chlorthalidone, hydrochlorothiazide), sympatholitics, endothelinantagonists; agents that enhance ABCA1 gene expression; cholesterylester transfer protein (CETP) inhibiting compounds, includinganacetrapib; 5-lipoxygenase activating protein (FLAP) inhibitingcompounds, 5-lipoxygenase (5-LO) inhibiting compounds, farnesoid Xreceptor (FXR) ligands including both antagonists and agonists; Liver XReceptor (LXR)-alpha ligands, LXR-beta ligands, bisphosphonate compoundssuch as alendronate sodium; cyclooxygenase-2 inhibitors such asrofecoxib and celecoxib; and compounds that attenuate vascularinflammation.

Throughout the synthetic schemes and examples, abbreviations are usedwith the following meanings unless otherwise indicated:

-   ABCA1 is adenosyltriphosphate-binding cassette-family A1-   Ac is acetate, acetyl;-   ACN is acetonitrile;-   aq. is aqueous;-   Ar is Aryl;-   Bn is benzyl;-   Boc is tertbutylcarbamoyl;-   Bu is butyl;-   CD-FBS is charcoal dextran treated fetal bovine serum-   CHO is Chinese hamster ovary-   cpm is counts per minute;-   ° C. is degrees Celsius-   δ is chemical shift;-   ^(c)Pr is cyclopropyl;-   DCM is dichloromethane;-   DMF is N,N-dimethylformamide;-   DMSO is dimethyl sulfoxide;-   dppf is 1,1′-bis(diphenylphosphino)ferrocene;-   ES-MS is electrospray ion-mass spectroscopy;-   Et is ethyl;-   F12FBS is F12K media containing fetal bovine serum;-   F12K is Kaighn's Modification of Ham's F-12 Medium;-   FBS is fetal bovine serum;-   FXR is farnesoid X receptor;-   HATU is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate;-   HMG-CoA is 3-hydroxy-3-methyl-glutaryl coenzyme A;-   ¹HNMR is proton nuclear magnetic resonance;-   HPLC is high performance liquid chromatography;-   Hz is hertz;-   i is Iso;-   iPr₂NEt is diisopropylethyl amine;-   IP is the inflection point for a given dose-response titration    curve;-   kg is kilogram;-   LC/MS is Liquid chromatography/Mass Spectroscopy;-   LTB₄ is leukotriene B₄;-   LXR is liver X receptor;-   M is molar;-   Me is methyl;-   μg is microgram;-   MeCN is acetonitrile;-   MeOH is methanol;-   MHz is megahertz;-   mm is millimeter;-   μL is microliter;-   mM is milimolar;-   MS is mass spectrum, and a mass spectrum obtained by ES-MS may be    denoted herein by “ES”;-   mw is microwave;-   m/z is mass to charge ratio;-   n is normal;-   nm is nanometer;-   nPr is n-propyl;-   p is para;-   PBS is phosphate-buffered saline.-   Ph is phenyl;-   PPARα is peroxisome proliferator activated receptor alpha;-   Pr is propyl;-   RP-HPLC is reverse phase high performance liquid chromatography;-   rt is room temperature;-   sec is secondary;-   SFC is supercritical fluid chromatography;-   ^(t)Bu is tert-butyl;-   tert is tertiary;-   TFA is trifluoroacetic acid;-   THF is tetrahydrofuran;-   TMSCHN₂ is trimethylsilyldiazomethane;-   U is units;-   UV is ultraviolet.

SCHEMES

Synthetic methods for preparing the compounds of the present inventionare illustrated in the following Schemes and Examples. Startingmaterials are commercially available or may be made according toprocedures known in the art or as illustrated herein.

Reaction schemes 1-7 illustrate the methods employed in the synthesis ofthe compounds of Formula I. All abbreviations are as defined aboveunless indicated otherwise. In the Schemes, all substituents are asdefined above in Formula I unless indicated otherwise.

As shown in SCHEME 1, diethyl malonate derivative 1a was treated withcesium fluoride and oxidized in the presence of air to afford hydroxymalonate 1b. Treatment of 1b with isocyanate 1c, followed by cyclizationyielded oxazolidine dione 1d. Ethyl ester 1d was resolved using a chiralSFC method to afford intermediate A.

As shown in SCHEME 2, treatment of ethyl ester 1b with aqueous potassiumhydroxide provided carboxylic acid 2a. Acid 2a was treated withN-hydroxysuccinimide to give activated ester 2b, which was then reactedwith hydrazine to generate hydrazide 2c. Hydrazide 2c was subsequentlycondensed with an alkyl nitrile under basic conditions to form1,2,4-triazole 2d, which was esterafide using trimethylsilyldiazomethaneto give methyl ester 2e. Hydroxy ester 2e was then reacted with anisocyanate, undergoing a tandem intramolecular cyclization to giveoxazolidinedione 2f.

Intermediates of the formula B are known in the literature or may beconveniently prepared by a variety of methods familiar to those skilledin the art. One common route is illustrated in SCHEME 3. Amino-malonate3a is treated with benzyl bromide in the presence of base, such assodium ethoxide, in a suitable solvent, such as ethanol to provide 3b.Removal of the Boc protecting group using acid, such as trifluoroaceticacid affords amine 3c. Amine 3c is reacted with an appropriateisocyanate, such as 3f, in a suitable solvent, such asN,N-dimethylormamide, in the presence of base, such asdiisopropylethylamine to afford urea 3d. Urea 3d is converted toIntermediate B by treatment of 3d with base, such as aqueous lithiumhydroxide, in a suitable solvent, such as methanol, tetrahydrofuran or acombination of both.

As illustrated in SCHEME 4, compounds of the formula 4b can be preparedby first treatment of Intermediate B with substituted amines, such as 4cby a variety of methods familiar to those skilled in the art to affordamide 4a. Amide 4a can be cyclized under a variety of methods familiarto those skilled in the art, to provide heterocycle 4b.

As illustrated in SCHEME 5, the compounds of the present invention withstructural formula 5c may be prepared from Intermediate A by firstaddition of hydrazine in a suitable solvent such as methanol to affordIntermediate C. Treatment of C with a suitable carboxylic acid,carboxylic acid chloride, or carboxylic acid anhydride in the presenceof a suitable coupling reagent such asO-(7-azabensotriazol-1yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and a suitable base such asN,N-diisopropylethylamine provides 5a. Compound 5a can be cyclized tooxadiazole 5b via appropriate methods such as treatment withtriphenylphosphine in the presence of iodine and a suitable base such asN,N-diisopropylethylamine.

As illustrated in SCHEME 6, the compounds of the present invention withstructural formula 6c may be prepared from Intermediate A by firstheating in the presence of amino alcohol 6d in a suitable solvent suchas ethanol to provide 6a. Oxidation of alcohol 6a with an oxidant suchas Dess-Martin periodinane, in a suitable solvent such dichloromethaneprovides 6b. Reaction of 6b under appropriate cyclization conditionsfamiliar to those skilled in the art, provides heterocycle 6c.

Compound 7a can be prepared as described in SCHEME 7, by heatingIntermediate A with 7b in a suitable solvent, such as 2-methoxylethanol.

The following examples are provided so that the invention might be morefully understood. Unless otherwise indicated, the starting materials arecommercially available. They should not be construed as limiting theinvention in any way.

REPRESENTATIVE EXAMPLES

The following examples are provided to more fully illustrate the presentinvention, and shall not be construed as limiting the scope in anymanner. Unless stated otherwise:

-   All operations were carried out at room or ambient temperature (rt),    that is, at a temperature in the range 18-25° C.;-   Reactions are generally done using commercially available anhydrous    solvents under an inert atmosphere, either nitrogen or argon;-   Microwave reactions were done using a Biotage Initiator™ or CEM    Explorer® system;-   Evaporation of solvent was carried out using a rotary evaporator    under reduced pressure (4.5-30 mmHg) with a bath temperature of up    to 50° C.;-   The course of reactions was followed by thin layer chromatography    (TLC) and/or tandem high performance liquid chromatography (HPLC)    followed by electron spray mass spectroscopy (MS), herein termed    LCMS, and any reaction times are given for illustration only;-   The structure of all final compounds was assured by at least one of    the following techniques: MS or proton nuclear magnetic resonance    (1H NMR) spectrometry, and the purity was assured by at least one of    the following techniques: TLC or HPLC;-   ¹H NMR spectra were recorded on either a Varian Unity or a Varian    Inova instrument at 400, 500 or 600 MHz using the indicated solvent;    when line-listed, NMR data is in the form of delta values for major    diagnostic protons, given in parts per million (ppm) relative to    residual solvent peaks (multiplicity and number of hydrogens);    conventional abbreviations used for signal shape are: s. singlet; d.    doublet (apparent); t. triplet (apparent); m. multiplet; br. broad;    etc.; MS data were recorded on a Waters Micromass unit, interfaced    with a Hewlett-Packard (Agilent 1100) HPLC instrument, and operating    on MassLynx/OpenLynx software; electrospray ionization was used with    positive (ES+) or negative ion (ES−) detection; and diode array    detection.-   Purification of compounds by preparative reverse phase HPLC was    performed on a Gilson system using a YMC-Pack Pro C18 column (150×20    mm i.d.) eluting at 20 mL/min with a water/acetonitrile (0.1% TFA)    gradient (5% acetonitrile to 95% acetonitrile) or on a Shimadzu    system using a Sunfire Prep C18 OBD 5 μM column (100×30 mm i.d.)    eluting at 50 mL/min with a water/acetonitrile (0.1% TFA) gradient;-   Purification of compounds by preparative thin layer chromatography    (PTLC) was conducted on 20×20 cm glass plates coated with silica    gel, commercially available from Analtech; or E. Merck.-   Flash column chromatography was carried out on a glass silica gel    column using Kieselgel 60, 0.063-0.200 mm (SiO₂), or on a Biotage    SiO₂ cartridge system using the Biotage Horizon and Biotage SP-1    systems; or a Teledyne Isco SiO₂ cartridge using the CombiFlashRf    system; Chemical symbols have their usual meanings, and the    following abbreviations have also been used: h (hours), min    (minutes), d (days), v (volume), w (weight), b.p. (boiling point),    m.p. (melting point), L (litre(s)), mL (millilitres), g (gram(s)),    mg (milligrams(s)), mol (moles), mmol (millimoles), eq or equiv    (equivalent(s)), IC50 (molar concentration which results in 50% of    maximum possible inhibition), EC50 (molar concentration which    results in 50% of maximum possible efficacy), μM (micromolar), nM    (nanomolar).

In the Tables in the following Examples, compounds having mass spectraldata were synthetically prepared.

Intermediate A Ethyl(5R)-benzyl-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxylate

Step A: Diethyl benzyl(hydroxy)propanedioate

A mixture of diethyl benzylpropanedioate (41 g) and CsF (49.8 g) in 90mL of DMF was heated at 40° C. with vigorous air bubbling for 3 days.The resulting mixture was diluted with ethyl acetate (800 mL) and washedwith water (3×1 L). The organic layer was concentrated and then purifiedby Biotage silica gel column chromatography (5-20% ethyl acetate inhexanes) to give the title product as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ: 7.22-7.26 (m, 5H), 4.23 (q, J=7.2 Hz, 4H), 3.80 (br, 1H), 3.35(s, 2H), 1.26 (t, J=7.2 Hz, 6H).

Step B: Ethyl5-benzyl-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxylate

To a mixture of NaOH (25 g) and 15.7 g of activated molecular sieves in1159 mL of THF at 0° C. was added a 1159 mL THF solution of diethylbenzyl(hydroxy)propanedioate (153 g). After 5 min, to this mixture wasadded [(1R)-1-isocyanatoethyl]benzene (118 g). The mixture was stirredat 0° C. for 30 min and then warmed to ambient temperature and stirredfor 4 h. The reaction mixture was directly purified using a Biotagesilica gel chromatography system (5-30% ethyl acetate in hexanes) togive the title compound.

Step C: Ethyl(5R)-benzyl-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxylate

The purification of ethyl5-benzyl-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxylateby chiral SFC following the conditions below provided the title compoundas a single diastereomer. ¹H NMR: 400 MHz, CDCl₃) δ: 7.170-7.253 (m,8H), 6.957-6.980 (m, 2H), 5.018 (q, J=7.2 Hz, 1H), 4.196-4.337 (m, 2H),3.545 (d, J=14.4 Hz, 1H), 3.401 (d, J=14.4 Hz, 1H), 1.503 (d, J=7.6 Hz,3H), 1.242 (t, J=7.6 Hz, 3H).

-   Chiral SFC (Supercritical Fluid Chromatography) Separation    conditions:-   Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd.-   Column: AD 250 mm×50 mm-   Mobile phase: A: Supercritical CO₂, B: MeOH, A:B=75:25 at 160 mL/min-   Column Temp: 38° C.-   Nozzle Pressure: 100 Bar-   Nozzle Temp: 60° C.-   Evaporator Temp: 20° C.-   Trimmer Temp: 25° C.-   Wavelength: 220 nm

Intermediate B Lithium4-benzyl-2,5-dioxo-1-[(1R)-1-phenylethyl]imidazolidine-4-carboxylate

Step A: Diethylbenzyl[(tert-butoxycarbonyl)amino]propanedioate

To diethyl[(tert-butoxycarbonyl)amino]propanedioate (5.56 mL, 21.79mmol) in ethanol (30 ml) was added sodium ethoxide (9.76 ml, 26.2 mmol)followed by benzyl bromide (2.59 mL, 21.79 mmol). The mixture wasstirred for 6 h, and the solvent was removed in vacuo. Saturated aqueoussodium hydrogen carbonate (50 mL) was added and the mixture wasextracted with ethyl acacate (3×50 mL). The combined organic fractionswere washed with saturated aqueous brine (1×50 mL), dried with anhydroussodium sulfate, filtered and the solvent removed in vacuo to afford thetitle compound as a colorless amorphous solid. LC/MS 366.1 (M+1).

Step B: Diethylamino(benzyl)propanedioate trifluoroacetate

To the product of Step A (7.5 g, 20.52 mmol) in dichloromethane (24 mL)was added trifluoroacetic acid (12 mL, 156 mmol) and the mixture stirredfor 1 h. The solvent was removed in vacuo and the oil azeotroped withtoluene (2×20 mL) to afford the title compound as a tan amorphous solid.LC/MS 266.1 (M+1).

Step C: Diethylbenzyl({[(1R)-1-phenylethyl]carbamoyl}amino)propanedioate

To the product from Step B (7.79 g, 20.54 mmol) in N,N-dimethylormamide(100 mL) was added diisopropylethylamine (10.76 mL, 61.6 mmol) at 0° C.the mixture was stirred for 5 min then (R)-(+)-1-phenylethyl isocyanate(3.76 mL, 26.7 mmol) was added dropwise. The mixture was warmed toambient temperature over 30 min and stirred for 16 h. Water (150 mL) wasadded and a white solid crashed out, the mixture was filtered and thesolid washed with water. The solid was diluted in ethyl acetate (250 mL)and half saturated aqueous sodium hydrogen carbonate (200 mL) was addedand the mixture was extracted with ethyl acetate (4×50 mL). The combinedorganic fractions were washed with brine (saturated, 1×100 mL), driedwith anhydrous sodium sulfate, filtered and the solvent removed in vacuoto afford the title compound as a colorless amorphous solid. LC/MS 413.1(M+1).

Step D: Lithium4-benzyl-2,5-dioxo-1-[(1R)-1-phenylethyl]imidazolidine-4-carboxylate

To a solution of the product from Step C (7.8 g, 18.91 mmol) intetrahydrofuran (60 mL) and methanol (20.00 mL) was added a 1 M lithiumhydroxide solution (19.86 mL, 19.86 mmol) and the mixture stirred for 30min. The solvent was removed in vacuo and the residue azeotroped withtoluene (3×25 mL) to afford the title compound as a colorless amorphoussolid. LC/MS 339.1 (M+1).

Intermediate C

(5S)-5-Benzyl-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carbohydrazide

To a slurry of Intermediate A (4 g, 10.89 mmol) in methanol (18 mL) wasadded anhydrous hydrazine (0.376 mL, 11.98 mmol) and the mixture wassonicated for 1 h. The solvent was removed in vacuo to afford the crudetitle compound as a colorless solid. LC/MS 354.1 (M+1).

Example 1

5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione(Compound 1) Step A: Ethyl2-benzyl-3-hydrazinyl-2-hydroxy-3-oxopropanoate

A mixture of 2-benzyl-3-ethoxy-2-hydroxy-3-oxopropanoic acid (250 mg),HATU (479 mg), diisopropylethyl amine (149 mg) and N-hydroxysuccinamide(145 mg) in 4 mL of DMF was stirred at ambient temperature for 1.5 h.The mixture was diluted with ethyl acetate, washed with water. Theorganic layer was dried with magnesium sulfate and concentrated to givethe desired product ethyl2-benzyl-3-hydrazinyl-2-hydroxy-3-oxopropanoate (352 mg), which wasdirectly used for the next step. To ethyl2-benzyl-3-hydrazinyl-2-hydroxy-3-oxopropanoate (352 mg) in DCM (5 mL)was added hydrazine (anhydrous, 101 mg) at ambient temperature.Instantaneously the solution turned cloudy and after 15 min the solventwas removed in vacuo to afford the crude title compound as an amorphoussolid. LC/MS 275.2 (M+23).

Step B: Methyl2-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-2-hydroxy-3-phenylpropanoate

To the mixture of ethyl 2-benzyl-3-hydrazinyl-2-hydroxy-3-oxopropanoate(40 mg), 3,5-dimethoxybenzonitrile (55 mg) and K₂CO₃ (44 mg) in 2 mL ofn-butanol was heated at 160° C. for 1.5 h. The mixture was then dilutedwith ethyl acetate and water. The aqueous layer was washed with ethylacetate and then acidified until pH=1. The mixture was then extractedwith 30% isopropanol in chloroform. The organic layer was dried withmagnesium sulfate and concentrated to give the crude acid, which wasthen dissolved in methanol. To the resulting solution was added TMSCHN₂(0.3 mL, 2 M in Et2O) at rt. After 30 min, the mixture was concentratedand purified by Gilson RP-HPLC (30-100% ACN/water/0.05% TFA) to givemethyl2-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-2-hydroxy-3-phenylpropanoateas a yellow oil.

Step C:5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione

To a solution of methyl2-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-2-hydroxy-3-phenylpropanoate(7 mg) in 1 mL of THF was added NaOH (4 mg) and(R)-1-fluoro-4-(1-isocyanatoethyl)benzene (15 mg). The resulting mixturewas stirred at ambient temperature overnight. The resulting mixture wasdiluted with ethyl acetate, and then quenched with water. The organiclayer was concentrated and purified by reverse phase HPLC (YMC Pro-C18column, gradient elution, 30% to 100% acetonitrile/water with 0.1% TFA)to give the title compound. LC/MS 517.2 (M+1). IC₅₀ value=C rating.

Example 2(5R)-5-Benzyl-5-[5-(3,5-dimethoxybenzyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione(Compound 2)

Step A:(5S)-5-Benzyl-N-[(3,5-dimethoxyphenyl)acetyl]-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carbohydrazide

To Intermediate C (75 mg, 0.212 mmol) in dichloromethane (2 ml), wasadded (3,5-dimethoxyphenyl)acetic acid (51.0 mg, 0.255 mmol),N,N-diisopropylethylamine (0.074 mL, 0.424 mmol, andO-(7-azabensotriazol-1yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (105 mg, 0.276 mmol) sequentially. The mixture wasstirred at ambient temperature for 1.5 h and saturated aqueous sodiumhydrogen carbonate (5 mL) added. The layers were separated and theaqueous phase extracted with dichloromethane (3×5 mL). The combinedorganic phases were washed with saturated aqueous brine (1×5 mL), driedwith anhydrous sodium sulfate, filtered and the solvent removed invacuo. The yellow oil was purified by column chromatography (silica gel40 g column) eluting with ethyl acetate/hexane (gradient from 0% to 70%)to give the title compound as a colorless amorphous solid. LC/MS 532.1(M+1).

Step B:(5R)-5-Benzyl-5-[5-(3,5-dimethoxybenzyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

To Iodine (102 mg, 0.400 mmol) in dichloromethane (2 mL) was addedtriphenylphosphine (108 mg, 0.41 mmol). After 5 min triethylamine (0.112mL, 0.8 mmol) was added. After 5 min a solution of the product from StepA (53.2 mg, 0.1 mmol) in dichloromethane (2 mL) was added. Afterstirring at ambient temperature for 1 h, a 1:1 mixture of saturatedaqueous sodium hydrogen carbonate and saturated aqueous sodiumthiosulfate (5 mL) was added. The biphasic mixture was stirred for 10min, the layers were separated and the aqueous phase extracted withdichloromethane (3×5 mL). The combined organic phases were washed withsaturated aqueous brine (1×5 mL), dried with anhydrous sodium sulfate,filtered and the solvent removed in vacuo. The yellow oil was purifiedby reverse phase HPLC (YMC Pro-C 18 column, gradient elution, 20% to100% acetonitrile/water with 0.1% TFA) to afford the title compound as acolorless amorphous solid. LC/MS 514.1 (M+1). IC50 value=A rating.

Following the procedures described above, but using the appropriatelysubstituted carboxylic acid, the compounds in Table 1 below were made.

TABLE 1 Exact Compound IC₅₀ Mass Number Rating Structure IUPAC Name [M +H]+ 3 B

(5R)-5-Benzyl-5-(5- benzyl-1,3,4- oxadiazol-2-yl)-3-[(1R)-1-phenylethyl]- 1,3-oxazolidine-2,4- dione 454.1 4 A

(5R)-5-Benzyl-5-[5- (3,5- dimethoxyphenyl)- 1,3,4-oxadiazol-2-yl]-3-[(1R)-1- phenylethyl]-1,3- oxazolidine-2,4-dione 500.1 5 A

(5R)-5-Benzyl-5-[5-(1- phenylcyclopropyl)- 1,3,4-oxadiazol-2-yl]-3-[(1R)-1- phenylethyl]-1,3- oxazolidine-2,4-dione 480.1 6 B

(5R)-5-Benzyl-3-[(1R)- 1-phenylethyl]-5-(3- phenyl-1,2,4-oxadiazol-5-yl)-1,3- oxazolidine-2,4-dione 440.1 7 C

(5R)-5-Benzyl-3-[(1R)- 1-phenylethyl]-5-(5- pyridin-4-yl-1,3,4-oxadiazol-2-yl)-1,3- oxazolidine-2,4-dione 441.1 8 B

(5R)-5-Benzyl-5-[5- (4,6- dimethoxypyrimidin-2- yl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1- phenylethyl]-1,3- oxazolidine-2,4-dione 502.1 9 B

(5R)-5-Benzyl-5-{5-[1- (3,5- difluorophenyl) cyclopropyl]-1,3,4-oxadiazol- 2-yl}-3-[(1R)-1- phenylethyl]-1,3-oxazolidine-2,4-dione 516.1 10 B

(5R)-5-[5-(3-Amino-5- methoxyphenyl)-1,3,4- oxadiazol-2-yl]-5-benzyl-3-[(1R)-1- phenylethyl]-1,3- oxazolidine-2,4-dione 485.1 11 C

(5R)-5-Benzyl-3-[(1R)- 1-phenylethyl]-5-[5- (2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]- 1,3-oxazolidine-2,4- dione 446.1 12 C

(5R)-5-Benzyl-3-[(1R)- 1-phenylethyl]-5-{5-[1- (trifluoromethyl)cyclopropyl]-1,3,4- oxadiazol-2-yl}-1,3- oxazolidine-2,4-dione 472.1 13B

(5R)-5-Benzyl-5-[5- (cyclopropylmethyl)- 1,3,4-oxadiazol-2-yl]-3-[(1R)-1- phenylethyl]-1,3- oxazolidine-2,4-dione 418.1 14 B

(5R)-5-Benzyl-3-[(1R)- 1-phenylethyl]-5-[5-(1- pyridin-4-ylcyclopropyl)-1,3,4- oxadiazol-2-yl]-1,3- oxazolidine-2,4-dione 481.1

Example 3(5R)-5-Benzyl-5-[4-(3,5-dimethoxyphenyl)-1H-imidazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione(Compound 15)

Step A:(5R)-5-Benzyl-N-[2-(3,5-dimethoxyphenyl)-2-hydroxyethyl]-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxamide

To Intermediate A (250 mg, 0.680 mmol) in ethanol (3 mL) was added2-hydroxy-2-(3,5-dimethoxyphenyl)ethylamine (268 mg, 1.361 mmol) and themixture was heated at 70° C. for 2 h. The solvent was removed and theresidue was purified by column chromatography (silica gel 40 g column)eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give thetitle compound as a colorless amorphous solid. LC/MS 519.1 (M+1).

Step B:(5R)-5-Benzyl-N-[2-(3,5-dimethoxyphenyl)-2-oxoethyl]-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxamide

To the product from Step A (310 mg, 0.598 mmol) in dichloromethane (5mL) was added Dess-Martin periodinane (392 mg, 0.897 mmol) and themixture was stirred for 30 min. A 1:1 mixture of saturated aqueoussodium bicarbonate and saturated aqueous sodium thiosulfate (20 mL) wasadded and the mixture was stirred rapidly for 15 min. The layers wereseparated and the aqueous phase extracted with dichloromethane (3×10mL). The combined organic phases were washed with saturated aqueousbrine (1×15 mL), dried with anhydrous sodium sulfate, filtered and thesolvent removed in vacuo, to afford the crude colorless title compoundas an amorphous solid. LC/MS 517.1 (M+1).

Step C:(5R)-5-Benzyl-5-[4-(3,5-dimethoxyphenyl)-1H-imidazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

To the product from Step B (40 mg, 0.077 mmol) in acetic acid (1 mL) wasadded ammonium acetate (179 mg, 2.323 mmol) and the mixture heated at100° C. for 40 h. The solvent was removed and the yellow oil waspurified by reverse phase HPLC(YMC Pro-C 18 column, gradient elution,20% to 90% acetonitrile/water with 0.1% TFA) to afford the titlecompound as a colorless amorphous solid. LC/MS 498.1 (M+1). IC₅₀ value=Brating

Using the procedures described above, the following Examples in theattached Table were made.

TABLE 2 Exact Compound IC₅₀ Mass Number Rating Structure IUPAC Name [M +H]+ 16 B

(5R)-5-Benzyl-3-[(1R)-1- phenylethyl]-5-(5-phenyl-1H-imidazol-2-yl)-1,3- oxazolidine-2,4-dione 438.1 17 B

(5R)-5-Benzyl-5-(5- benzyl-1H-imidazol-2- yl)-3-[(1R)-1-phenylethyl]-1,3- oxazolidine-2,4-dione 452.1

Example 4(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(4-phenyl-1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione(Compound 18)

Step A:(5R)-5-Benzyl-N-(2-hydroxy-1-phenylethyl)-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxamide

To Intermediate A (200 mg, 0.544 mmol) in ethanol (2 mL) was added2-phenylglycinol (373 mg, 2.72 mmol) and the mixture was heated at 70°C. for 2 h. The solvent was removed and the residue was purified bycolumn chromatography (silica gel 40 g column) eluting with ethylacetate/hexane (gradient from 0% to 50%) to give the title compound as acolorless amorphous solid. LC/MS 459.1 (M+1).

Step B:(5R)-5-Benzyl-2,4-dioxo-N-(2-oxo-1-phenylethyl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxamide

To the product from Step A (250 mg, 0.545 mmol) in dichloromethane (5mL) was added Dess-Martin periodinane (358 mg, 0.818 mmol) and themixture was stirred for 30 min. A 1:1 mixture of saturated aqueoussodium bicarbonate and saturated aqueous sodium thiosulfate (20 mL) wasadded and the mixture was stirred rapidly for 15 min. The layers wereseparated and the aqueous phase extracted with dichloromethane (3×10mL). The combined organic phases were washed with saturated aqueousbrine (1×15 mL), dried with anhydrous sodium sulfate, filtered and thesolvent removed in vacuo, to afford the crude colorless title compoundas an amorphous solid. LC/MS 457.1 (M+1).

Step C:(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(4-phenyl-1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione

To iodine (111 mg, 0.438 mmol) in dichloromethane (2 mL) was addedtriphenylphosphine (121 mg, 0.46 mmol). After 5 min triethylamine (0.122mL, 0.876 mmol) was added. After 5 min a solution of the product fromStep B (100 mg, 0.219 mmol) in dichloromethane (2 mL) was added. Afterstirring at ambient temperature for 1 h, a 1:1 mixture of saturatedaqueous sodium hydrogen carbonate and saturated aqueous sodiumthiosulfate (5 mL) was added. The biphasic mixture was stirred for 10min, the layers were separated and the aqueous phase extracted withdichloromethane (3×5 mL). The combined organic phases were washed withsaturated aqueous brine (1×5 mL), dried with anhydrous sodium sulfate,filtered and the solvent removed in vacuo. The yellow oil was purifiedby reverse phase HPLC(YMC Pro-C 18 column, gradient elution, 20% to 100%acetonitrile/water with 0.1% TFA) to afford the title compound as acolorless amorphous solid. LC/MS 439.1 (M+1). IC₅₀ value=C rating.

Example 5(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione(Compound 19)

Step A:(5R)-5-Benzyl-N-(2-hydroxy-2-phenylethyl)-2,4-dioxo-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxamide

To Intermediate A (200 mg, 0.544 mmol) in ethanol (3 mL) was added2-amino-1-phenylethanol (149 mg, 1.09 mmol) and the mixture was heatedat 70° C. for 2 h. The solvent was removed and the residue was purifiedby column chromatography (silica gel 40 g column) eluting with ethylacetate/hexane (gradient from 0% to 100%) to give the title compound asa colorless amorphous solid. LC/MS 459.1 (M+1).

Step B:(5R)-5-Benzyl-2,4-dioxo-N-(2-oxo-2-phenylethyl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-5-carboxamide

To the product from Step A (100 mg, 0.218 mmol) in dichloromethane (3mL) was added Dess-Martin periodinane (143 mg, 0.327 mmol) and themixture was stirred for 30 min. A 1:1 mixture of saturated aqueoussodium bicarbonate and saturated aqueous sodium thiosulfate (10 mL) wasadded and the mixture was stirred rapidly for 15 min. The layers wereseparated and the aqueous phase extracted with dichloromethane (3×10mL). The combined organic phases were washed with saturated aqueousbrine (1×15 mL), dried with anhydrous sodium sulfate, filtered and thesolvent removed in vacuo, to afford the crude colorless title compoundas an amorphous solid. LC/MS 457.1 (M+1).

Step C:(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione

To the product of Step B (40 mg, 0.088 mmol) was added concentratedsulfuric acid (0.5 mL, 9.38 mmol) and the mixture stirred for 16 h. Icewas added followed by saturated aqueous sodium hydrogen carbonate (30mL) and the mixture was extracted with ethyl acetate (3×10 mL). Thecombined organic fractions were washed with saturated aqueous brine(1×15 mL), dried with anhydrous sodium sulfate, filtered and the solventremoved in vacuo. The yellow oil was purified by reverse phase HPLC(YMCPro-C 18 column, gradient elution, 20% to 100% acetonitrile/water with0.1% TFA) to afford the title compound as a colorless amorphous solid.LC/MS 439.1 (M+1). IC₅₀ value=C rating

The following Example in the attached Table was made by essentiallyfollowing the same procedures described above.

TABLE 3 Exact Compound IC₅₀ Mass Number Rating Structure IUPAC Name [M +H]+ 20 B

(5R)-5-Benzyl-5-(5- benzyl-1,3-oxazol-2-yl)- 3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 453.1

Example 6(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(3-phenyl-1H-1,2,4-triazol-5-yl)-1,3-oxazolidine-2,4-dione(Compound 21)

To Intermediate A (150 mg, 0.408 mmol) in 2-methoxylethanol (2 mL) wasadded benzenecarboximidohydrazide hydroiodide (107 mg, 0.408 mmol)followed by N,N-diisopropylethylamine (0.071 mL, 0.408 mmol). Themixture was heated at 70° C. for 1 h, and the solvent removed in vacuo.The yellow oil was purified by reverse phase HPLC(YMC Pro-C18 column,gradient elution, 55% to 85% acetonitrile/water with 0.1% TFA) to affordthe title compound as a colorless amorphous solid. LC/MS 439.1 (M+1).IC₅₀ value=C Rating

Example 7(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione(Compound 22)

Step A:4-Benzyl-N′-[(3,5-dimethoxyphenyl)carbonyl]-2,5-dioxo-1-[(1R)-1-phenylethyl]imidazolidine-4-carbohydrazide

To Intermediate A (200 mg, 0.581 mmol), 3,5-dimethoxybenzhydrazide (125mg, 0.639 mmol) in N,N-dimethylformamide (2.5 mL) was addedN,N-diisopropylethylamine (0.152 mL, 0.871 mmol) andO-(7-azabensotriazol-1yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (265 mg, 0.697 mmol) sequentially. The reactionmixture was stirred for 16 h, diluted with ethyl acetate (50 mL), washedwith water (2×10 mL), saturated aqueous brine (1×10 mL), dried withanhydrous sodium sulfate, filtered and the solvent removed in vacuo. Theresidue was purified by column chromatography (silica gel 40 g column)eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give thetitle compound as a colorless amorphous solid. LC/MS 517.1 (M+1).

Step B:(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione

To a stirring solution of iodine (354 mg, 1.394 mmol) in dichloromethane(8 mL) was added triphenylphosphine (375 mg, 1.429 mmol). After 5 mintriethylamine (0.389 mL, 2.79 mmol) was added. After 5 min a solution ofthe product from Step A (180 mg, 0.348 mmol) in dichloromethane (3 mL)was added. After stirring at ambient temperature for 1 h, a 1:1 mixtureof saturated aqueous sodium hydrogen carbonate and saturated aqueoussodium thiosulfate (5 mL) was added. The biphasic mixture was stirredfor 10 min, the layers were separated and the aqueous phase extractedwith dichloromethane (3×5 mL). The combined organic phases were washedwith saturated aqueous brine (1×5 mL), dried with anhydrous sodiumsulfate, filtered and the solvent removed in vacuo. The residue waspurified by column chromatography (silica gel 40 g column) eluting withethyl acetate/hexane (gradient from 0% to 100%) to give a mixture ofdiastereomers as a colorless amorphous solid. The isomers were separatedvia chiral HPLC (ChiralPak AS-H; 40% 2:1 methanol:acetonitrile/carbondioxide) to afford the first eluting isomer(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione(2.25 minutes) and the second eluting isomer(5S)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione(3.45 minutes) as colorless amorphous solids. LC/MS 499.1 (M+1). IC₅₀value=C rating for the title compound.

Biological Assay

The activity of the compounds of the present invention regardingmineralocorticoid receptor antagonism was evaluated using the followingassay.

Assessment of Mr Potency in HMN NH Pro Assay

The human MR NH Pro assay is a commercially available PathHunter™Protein: Protein interaction assay (DiscoveRx;http://www.discoverx.com/nhrs/prod-nhrs.php) that measures the abilityof compounds to antagonize full-length human Mineralocorticoid Receptor(MR) binding to a coactivator peptide. PathHunter™ CHO-K1 cells thatoverexpress human MR (Cat #93-0456C2, Lot No: 09B0913) were cultured ingrowth media (F12K w/Glutamine and phenol red (Gibco 11765-047)supplemented with 10% HI FBS (Gibco 16000); 0.25 mg/ml Hygromycin in PBS(Invitrogen 10687-010, 50 mg/ml); 100 I.U./mL and 100 μg/mL Pen/Strep(Gibco 15140-122); 0.6 mg/mL Geneticin).

Compounds were assessed for MR antagonist activity by incubating thecells with a titrating dose of compound in F12K w/Glutamine and phenolred culture media (Invitrogen 11765-047) supplemented with 1%Charcoal/Dextran Treated FBS (Hyclone #SH30068.01) and aldosterone (0.3nM) for 6 hours at 37° C. Cells were then treated with DiscoveRxdetection reagent for 1 hour at room temperature and read using anEnvision luminescence plate reader. % activity was measured relative tocells treated with aldosterone alone and IC₅₀ values were calculatedusing ADA software.

-   1. Growth Media:-   F12K w/Glutamine and phenol red (Gibco 11765-047)-   10% HI FBS (Gibco 16000)-   0.25 mg/ml Hygromycin in PBS (Invitrogen 10687-010, 50 mg/ml)-   100 I.U./mL and 100 μg/mL Pen/Strep (Gibco 15140-122)-   0.6 mg/mL Geneticin (Gibco 10131, 50 mg/ml)-   2. Assay Media:-   FI2K w/Glutamine and phenol red (Invitrogen 11765-047)-   1% Charcoal/Dextran Treated FBS (Hyclone #SH30068.01)-   3. 3× PathHunter Detection Reagents (Cat #93-0001) (need ˜6    ml/plate). Do not freeze and thaw the reagents more than 3 times.-   19× PathHunter Cell Assay Buffer-   5× Emerald II-   1× Galacton Star-   4. Control Agonist: Aldosterone: Sigma cat #A9477-   Prepare stock solution—10 μM in DMSO kept at −20° C.-   for assay, dilute in assay media to 1.8 or 6 nM (6× of final    concentration=about 0.3 nM to about 1.0 nM)-   5. Cell line: PathHunter CHO-K1 MR cells Cat #93-0456C2, Lot No:    09B0913, from operation liquid nitrogen stock.-   6. Control Antagonist: Spironolactone: Sigma #S-3378 and Eplerenone    Sigma #107724-20-9 (10 mM stock concentration also prepared in DMSO    and stored at −20° C.).    Methods:-   Assay Set Up and Calculations:-   1. Cells were grown in F12+FBS+Hygromycin+pen/strep+Genetin-   2. Cells were collected with 0.05% trypsin and the cell suspension    was spun and resuspended in a volume of F12+1.5% CD-FBS and counted.-   3. The cells were resuspended to 4×10⁵ cells/mL.-   4. Cells were (25 μL/well) added to the wells of a 384 well plate.-   5. The plate was then incubated at 37° C. over night in a humidified    incubator with 5% CO₂.-   6. Test compounds were titrated starting at 4.4 mM, 10-point    titration in 1:3 dilution.-   7. Aldosterone was diluted in assay media to 1.8 nM or 6 nM from 10    μM stock (final concentration to be about 0.3 nM to about 1.0 nM)    Protocol for 384 well plate format: 6 hr treatment:-   1. Plated 10K exponentially growing cells/well (25 μL) resuspended    in assay media to each well using the Multidrop (Thermo Electron)    (use white wall, clear bottom assay plates (Costar #3570) and    incubate overnight at 37° C., 5% CO₂.-   2. 0.25 μL 120× test compound (final DMSO concentration should be    <1%) was added to each well n=2, 10 point titrations starting at    36.7 μM final concentration.-   3. 5 μL 6× agonist (final aldosterone concentration should be about    0.3 nM to about 1.0 nM) was added to all wells using the PlateMate    Plus.

(ThermoFisher) (except those wells in columns 23 and 24)

-   4. 5 μL of assay media was added to all wells in column 23 and 24.-   5. Plates were incubated 6 hrs at 37° C., 5% CO₂.-   6. 15 μL 3× DiscoveRx detection reagent was added to each well.-   7. Plates were incubated for 1 hour at room temperature (plates    stored in the dark).-   8. Plates were read on Envision (PerkinElmer) luminesence plate    reader and analyzed using ADA.-   LC/MS method: (LC2M_Low/Medpositive mode).-   LC Conditions: 5-98% CH₃CN/H₂O+v 0.1% TFA over 1.25 min; Flow    Rate=1.5 mL/min, UV wavelength 254 nm; Column: Waters XTerra® MS C18    3.5 μm 2.1×20 mm IS™

As seen in the Examples above, compounds of the instant invention thathad an IC₅₀ value greater than 0 nM but less than 100 nM were given an“A” IC₅₀ rating. Compounds of the instant invention that had an IC₅₀value equal to, or greater than, 100 nM, but less than 500 nM, weregiven a “B” rating. Compounds of the instant invention that had an IC₅₀value equal to, or greater than 500 nM, but less than 2,000 nM, weregiven a “C” rating.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein X is NH or O;Each R¹ is independently halo, CF₃, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, orOR, wherein said alkyl and cycloalkyl are optionally substituted withone to three groups selected from halo, OR, CF₃, or CN; Each R isindependently H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or CF₃ wherein saidalkyl and cycloalkyl are optionally substituted with one to three groupsselected from halo, OH, C₁-C₆ alkoxy, CF₃, or CN; Each R^(a) isindependently H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, or CF₃ wherein saidalkyl and cycloalkyl are optionally substituted with one to three groupsselected from halo, OR, CF₃, or CN; Each R^(b) is independently H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, CF₃, or aryl, wherein said alkyl, cycloalkyland aryl are optionally substituted with one to three groups selectedfrom halo, OR, CF₃, or CN; R² is triazolyl, oxadiazolyl, imidazolyl,thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl or oxazolyl, wheretriazolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl,thiadiazolyl or oxazolyl is optionally substituted with one to twogroups from R⁵; R⁴ is H, C₁-C₆ alkyl, aryl, or C₃-C₁₀ cycloalkyl, wheresaid alkyl, aryl, or cycloalkyl is optionally substituted with one tofour groups selected from halo or OR; Each R⁵ is independently OR,(CR^(c) ₂)₀₋₃—CF₃, C₁-C₆ alkyl, (CR^(c) ₂)₀₋₃—C₃-C₁₀ cycloalkyl, (CR^(c)₂)₀₋₃-aryl, (CR^(c) ₂)₀₋₃-heteroaryl, or (CR^(c) ₂)₀₋₃-halo, where saidalkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with oneto three groups selected from optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, OR, halo,CF₃ or NH₂; and wherein said optionally substituted aryl, optionallysubstituted heteroaryl, or optionally substituted heterocyclyl areoptionally substituted one to four times by halo, CF₃, NH₂ or OR; EachR^(c) is independently H, C₁-C₆ alkyl, or C₃-C₁₀ cycloalkyl, whereinsaid alkyl and cycloalkyl are optionally substituted with one to threegroups selected from halo, OR, CF₃, or CN; m is 0, 1, 2 or 3; and p is0, 1, 2 or
 3. 2. The compound of Formula I, according to claim 1,wherein Each R^(a) is independently H or C₁-C₆ alkyl wherein said alkylis optionally substituted with one to three groups selected from halo,OR, CF₃, or CN; R² is triazolyl, oxadiazolyl, imidazolyl or oxazolyl,where triazolyl, oxadiazolyl, imidazolyl or oxazolyl is optionallysubstituted with one to two groups from R⁵; R⁴ is aryl or C₃-C₁₀cycloalkyl, where said aryl or cycloalkyl is optionally substituted withone to four groups selected from halo or OR; Each R⁵ is independentlyOR, C₁-C₆ alkyl, (CR^(c) ₂)₀₋₃—C₃-C₁₀ cycloalkyl, (CR^(c) ₂)₀₋₃-aryl,(CR^(c) ₂)₀₋₃-heteroaryl, or (CR^(c) ₂)₀₋₃-halo, where said alkyl,cycloalkyl, aryl or heteroaryl is optionally substituted with one tothree groups selected from aryl, heteroaryl, or heterocyclyl; m is 0 or1; and p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 3.A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein Each R¹ isindependently halo, CF₃, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or OR, whereinsaid alkyl and cycloalkyl are optionally substituted with one to threegroups selected from halo, OR, CF₃, or CN; Each R is independently H,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or CF₃ wherein said alkyl and cycloalkylare optionally substituted with one to three groups selected from halo,OR, CF₃, or CN; Each R^(b) is independently H or C₁-C₆ alkyl, whereinsaid alkyl is optionally substituted with one to three groups selectedfrom halo, OR, CF₃, or CN; Each R^(c) is independently H, C₁-C₆ alkyl,or C₃-C₁₀ cycloalkyl, wherein said alkyl and cycloalkyl are optionallysubstituted with one to three groups selected from halo, OR, CF₃, or CN;R² is triazolyl, oxadiazolyl, imidazolyl or oxazolyl, where triazolyl,oxadiazolyl, imidazolyl or oxazolyl is optionally substituted with oneto two groups from R⁵; R⁴ is C₁-C₆ alkyl, aryl, or C₃-C₁₀ cycloalkyl,where said alkyl, aryl, or cycloalkyl is optionally substituted with oneto four groups selected from halo or OR; Each R⁵ is independently(CR^(c) ₂)₀₋₃—CF₃, C₁-C₆ alkyl, (CR^(c) ₂)₀₋₃—C₃-C₁ cycloalkyl, (CR^(c)₂)₀₋₃aryl, (CR^(c) ₂)₀₋₃-heteroaryl, or (CR^(c) ₂)₀₋₃-halo, where saidalkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with oneto three groups selected from aryl, heteroaryl, heterocyclyl, OR, halo,CF₃ or NH₂; m is 0 or 1; and p is 1 or
 2. 4. The compound of claim 3,having the structural Formula II, wherein Each R^(b) is independently Hor C₁-C₆ alkyl; R⁴ is aryl, or C₃-C₁₀ cycloalkyl, where said aryl, orcycloalkyl is optionally substituted with one to four groups selectedfrom halo or OR; Each R⁵ is independently (CR^(c) ₂)₀₋₃—C₃-C₁₀cycloalkyl, (CR^(c) ₂)₀₋₃-aryl, or (CR^(c) ₂)₀₋₃-heteroaryl, where saidcycloalkyl, aryl or heteroaryl is optionally substituted with one tothree groups selected from aryl, heteroaryl, heterocyclyl, OR, halo, CF₃or NH₂; and p is 1; or a pharmaceutically acceptable salt thereof.
 5. Acompound which is Compound Number IUPAC Name 15-Benzyl-5-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione 2(5R)-5-Benzyl-5-[5-(3,5-dimethoxybenzyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 3(5R)-5-Benzyl-5-(5-benzyl-1,3,4-oxadiazol-2-yl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 4(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 5(5R)-5-Benzyl-5-[5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 6(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,3-oxazolidine-2,4-dione 7(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-pyridin-4-yl-1,3,4-oxadiazol-2-yl)-1,3-oxazolidine-2,4-dione 8(5R)-5-Benzyl-5-[5-(4,6-dimethoxypyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 9(5R)-5-Benzyl-5-{5-[1-(3,5-difluorophenyl)cyclopropyl]-1,3,4-oxadiazol-2-yl}-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 10(5R)-5-[5-(3-Amino-5-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-5-benzyl-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 11(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]-1,3-oxazolidine-2,4-dione 12(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-{5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl}-1,3-oxazolidine-2,4-dione 13(5R)-5-Benzyl-5-[5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 14(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-[5-(1-pyridin-4-ylcyclopropyl)-1,3,4-oxadiazol-2-yl]-1,3-oxazolidine-2,4-dione 15(5R)-5-Benzyl-5-[4-(3,5-dimethoxyphenyl)-1H-imidazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 16(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-1H-imidazol-2-yl)-1,3-oxazolidine-2,4-dione 17(5R)-5-Benzyl-5-(5-benzyl-1H-imidazol-2-yl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 18(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(4-phenyl-1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione 19(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione 20(5R)-5-Benzyl-5-(5-benzyl-1,3-oxazol-2-yl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 21(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(3-phenyl-1H-1,2,4-triazol-5-yl)-1,3-oxazolidine-2,4-dione 22(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim5, which is Compound Number IUPAC Name 15-Benzyl-5-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione 2(5R)-5-Benzyl-5-[5-(3,5-dimethoxybenzyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 3(5R)-5-Benzyl-5-(5-benzyl-1,3,4-oxadiazol-2-yl)-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 4(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 5(5R)-5-Benzyl-5-[5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 8(5R)-5-Benzyl-5-[5-(4,6-dimethoxypyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 13(5R)-5-Benzyl-5-[5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 15(5R)-5-Benzyl-5-[4-(3,5-dimethoxyphenyl)-1H-imidazol-2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione 22(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione

or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprised of the compound of Formula I of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 8. The pharmaceutical composition of claim 7comprising one or more pharmaceutically active agents in addition to thecompound of Formula I or a pharmaceutically acceptable salt thereof. 9.A method of treating heart failure, hypertension, atherosclerosis orprimary hyperaldosteronism in a human patient in need of, comprisingadministering to the patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 10. Amethod of treating metabolic syndrome in a mammal in need of suchtreatment, comprising administering to the mammal a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof.
 11. A method of treating a physiological orpathologic disease, selected from Conn's Syndrome, primary and secondaryhyperaldosteronism, increased sodium retention, increased magnesium andpotassium excretion (diuresis), increased water retention, hypertension(isolated systolic and combined systolic/diastolic), arrhythmias,myocardial fibrosis, myocardial infarction, and Bartter's Syndrome in ahuman patient in need of, comprising administering to the patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 12. A method of treating renalfailure in a human patient in need of such treatment comprisingadministering to the patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 13. Amethod for antagonizing aldosterone receptor (MR) and increasingaldosterone levels in a mammal in need thereof which comprisesadministering to said mammal a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof.